The inhalation route, employed primarily in the past for drugs acting in the respiratory tract, is now being extended for systemic drug delivery.
Water soluble drugs can be delivered to the lungs in droplets produced by aerosolizing a solution of the drug, using a nebulizer to generate and aerosolize the droplets. The aerosol formed by the nebulizer has a droplet size of approximately 1 to 50 microns, more commonly 1 to 10 microns in diameter, ideal for delivery to the lungs. For example, ribavirin (virazole) is a relatively water soluble drug (142 mg/mL) delivered via nebulizer in hospitals for treatment of respiratory syncytial virus and other viral diseases. However, this drug crystallizes wherever the nebulized mist lands, including but not limited to equipment, bedding, and the patient, thus creating a hazard to health workers, especially pregnant women.
Delivery of poorly water-soluble drugs presents an even bigger problem for aqueous aerosol delivery to the lungs as large drug particles block the nebulizer orifice.
Thus, there is a need for inhalation formulations with improved deposition efficiency, targeting, trafficking through the mucus membrane, biovailability, stability, particularly for higher solid formulations, and sustained release for inhaled drugs.
Various particle engineering methods have been developed to improve inhalation formulations.
For example, spray freeze drying into liquids, supercritical fluid technology, and crystal engineering, are being developed to overcome limitations of conventional methods of spray drying and jet milling.
Various engineered particles such as amorphous glass particles for protein stabilization, spray-dried oligosaccharides and large porous particles for sustained delivery, and nanocrystals for improved cellular penetration, are also being developed.
In addition, new dry powder and liquid aerosol inhalation devices, such as the Nektar DPI system, AERx® (Aradigm), Spiros® (Dura Pharmaceuticals), and the Respimat® (Boehringer Ingelheim) which improve deposition efficiency, ease of use, and/or reproducibility of dose have been developed.
SiRNA and poly(ethylene imine) (PEI), a water soluble polymer, form a complex in aqueous solution which has been nebulized and delivered into mice lungs, with activity of the SiRNA being maintained. Maintaining activity of siRNA can be problematic since SiRNA requires protection from nucleases as well as an appropriate delivery vector which allows for entry of siRNA into the cell followed by endosomal escape so that it can function in the cytosol of the cell.
U.S. Pat. No. 6,264,922 describes nebulized aerosols containing a nanoparticle dispersion of insoluble therapeutic or diagnostic agent particles having a surface modifier on the surface thereof.
Rudolph et el. (Pharmaceutical Research 2004 21(9):1662-1669) describe an aqueous dispersion of solid lipid nanoparticles (SLN) of cetylpalmitate and the cationic lipid N,N-di-(β-stearoylethyl)-N,N-dimethyl-ammonium chloride or 1,2-dioleyl-sn-glycero-3-trimethylammoniumpropane (DOTAP) to which DNA was adsorbed to the surface for lung delivery. They showed expression of the DNA-encoded protein after delivery from a nebulized aerosol to the lungs of mice.
Kawashima et al. discloses dispersions of PLGA nanoparticles containing insulin prepared by a modified emulsion solvent diffusion method in water, and delivered by nebulizer to the lungs of guinea pigs (Kawashima et al. Journal of Controlled Release 1999 62, no. 1-2 (6 ref.):279-287).
WO 94/20072 discloses colloidal solid lipid particles primarily for parenteral administration of preferably poorly water soluble bioactive substances.